Brain-derived neurotrophic factor (BDNF) belongs to a neurotrophin family together with nerve growth factor (NGF) and neurotrophin-3 (NT-3) and is a secretory protein produced in various cells such as nerve cell (neuron), glia cell (microglia, stellate cell, oligodendroglia, etc.), etc. BDNF is unevenly distributed in central nerve system centering on hippocampus and has been known to exhibit various physiological activities in nerve system such as existence and maintenance of nerve cells, adjustment of shape of neurite, adjustment of function of synapse, control of nerve reversibility, etc.
It has been known that BDNF expression in vivo is finally controlled by activation (phosphorylation) of a CREB (cAMP-response-element-binding protein) via intracellular signaling pathway called an MAP kinase (mitogen-activated protein kinase or MARK which is a protein activating the mitogenic factor)/CREB pathway being initiated by activation of TrkB (tropomyosin receptor kinase B) which is a highly affinitive receptor to BDNF. Thus, it has been said that, when BDNF binds to TrkB on cell surfaces so that TrkB is activated, there are induced CREB activation by an MEK (MAPK kinase or MAP kinase kinase)/ERK (extracellular-signal-regulated kinase) pathway and CREB activation by a PI3K (phosphoinositide 3-kinase)/Akt pathway (in the present application, both pathways are called MAP kinase/CREB pathway).
With regard to the MEK/ERK pathway, it has been said that, from activation of a Trk receptor, activation of various proteins such as Grb2/Sos, Ras, Raf, MEK1/2, ERK1/2, Rsk, etc. is successively transmitted and, finally, CREB is activated (phosphorylated) to express BDNF, etc. With regard to a PI3K/Akt pathway, it has been said that, due to activation of a Trk receptor, activation of proteins such as PI3K, Akt, P38MAPK, etc. is successively transmitted whereby phosphorylation of CREB is induced similarly.
The present inventors have found that an extract from inflamed tissues inoculated with vaccinia virus has an action to the expression of neurotrophic factor such as BDNF in cultured cells. They have further clarified that, during that time, the extract acts on various proteins in intracellular signaling pathway participating in the expression of BDNF, etc. and that those actions are suppressed by each of inhibitors to Trk receptor, PI3K, P38PAPK, MEK1/2, etc. The method of determination or evaluation according to the present invention is based on the study results as such.
The extract from inflamed tissues inoculated with vaccinia virus as an active ingredient in the ameliorating or therapeutic agent for chronic prostatitis, interstitial cystitis an/or urination disorders of the present invention (hereinafter referred to as “the medicinal agent of the present invention”) is disclosed to have the following effects: an analgesic effect, sedative effect, anti-stress effect and anti-allergic effect (see Patent Document 1); an immunostimulating effect, anti-cancer effect and cirrhosis inhibitory effect (see Patent Document 2); a treatment effect against idiopathic thrombocytopenic purpura (see Patent Document 3); a treatment effect against postherpetic neuralgia, brain edema, dementia, spinocerebellar degeneration and the like (see Patent Document 4); a treatment effect against Raynaud syndrome, diabetic neuropathy, sequelae of subacute myelo-optico-neuropathy and the like (see Patent Document 5); a kallikrein production inhibitory effect and peripheral circulatory disorder improving effect (see Patent Document 6); a bone atrophy improving effect (see Patent Document 7); a nitric oxide production inhibitory effect effective for the treatment of sepsis and endotoxic shock (see Patent Document 8); a treatment effect against osteoporosis (see Patent Document 9); a treatment effect against AIDS based on a Nef action inhibitory effect and chemokine production inhibitory effect (see Patent Documents 10 and 11); a treatment effect against ischemic disorders such as cerebral infarction (see Patent Document 12); a treatment effect against fibromyalgia syndrome (see Patent Document 13); and a treatment effect against infections (see Patent Document 14); prophylactic or alleviating effect for a peripheral nerve disorder induced by an anti-cancer agent (see Patent Document 15) and the like.
However, this is for the first time that the enhancement of BDNF expression by an extract from inflamed tissues inoculated with vaccinia virus and an adjusting action therefore are clarified and it has not been known up to now for a method of determining or evaluating the extract where the enhancement of BDNF expression, the enhancement of activations of various proteins in intracellular signaling pathway participating therein, etc. are used as indicators.